Effects of a histone deacetylase 3 inhibitor on extinction and reinstatement of cocaine self-administration in rats

Abstract

Rationale: A challenge in treating substance use disorder is that successful treatment often does not persist, resulting in relapse and continued drug seeking. One approach to persistently weaken drug-seeking behaviors is to pair exposure to drug-associated cues or behaviors with delivery of a compound that may strengthen the inhibition of the association between drug cues and behavior.

Objectives: We evaluated whether a selective histone deacetylase 3 (HDAC3) inhibitor could promote extinction and weaken contextual control of operant drug seeking after intravenous cocaine self-administration.

Methods: Male Long-Evans rats received a systemic injection of the HDAC3 inhibitor RGFP966 either before or immediately after the first extinction session. Persistence of extinction was tested over subsequent extinction sessions, as well as tests of reinstatement that included cue-induced reinstatement, contextual renewal, and cocaine-primed reinstatement. Additional extinction sessions occurred between each reinstatement test. We also evaluated effects of RGFP966 on performance and motivation during stable fixed ratio operant responding for cocaine and during a progressive ratio of reinforcement.

Results: RGFP966 administered before the first extinction session led to significantly less responding during subsequent extinction and reinstatement tests compared to vehicle-injected rats. Follow-up studies found that these effects were not likely due to a performance deficit or a change in motivation to self-administer cocaine, as injections of RGFP966 had no effect on stable responding during a fixed or progressive ratio schedule. In addition, RGFP966 administered just after the first extinction session had no effect during early extinction and reinstatement tests, but weakened long-term responding during later extinction sessions.

Conclusions: These results suggest that a systemic injection of a selective HDAC3 inhibitor can enhance extinction and suppress reinstatement after cocaine self-administration. The finding that behavioral and pharmacological manipulations can be combined to decrease drug seeking provides further potential for treatment by epigenetic modulation.

Keywords: Epigenetics; Extinction; Histone acetylation; Intravenous cocaine; Long-Evans rats.

Figure 1.. Effects of RGFP966 on extinction and reinstatement.

(A) Average active (reinforced, circles) and inactive (not reinforced, triangles) lever presses during the first three 2-hr extinction sessions (shown in 15-min time blocks). Rats received a single injection of Vehicle (VEH, N = 9) or RGFP966 (RGFP966, N = 9) 20 min prior to the first extinction session (Ext 1). (B) Responding during subsequent extinction and reinstatement sessions. Data are presented as means of the 2-hr sessions during additional extinction sessions (E4-E8, E9-E10, E11-E12, and E13), and reinstatement testing in a novel context (CTX), with the cue previously associated with cocaine (CUE), and following a priming injection of cocaine (COC). Error bars indicate the standard error of the mean (±SEM). * p<0.05, **p<0.005 (see text for statistical details).

Figure 2.. Acute effects of RGFP966 on asymptotic responding for cocaine on during an (A) FR5 or (B) progressive ratio schedule of reinforcement.

(A) Average active and inactive lever presses during fixed ratio (FR5) maintenance self-administration (2-hr duration) sessions that were preceded by no injection (baseline) or injection of vehicle or RGFP966 (n=7). (B) Average active and inactive lever presses during 3-hr progressive ratio sessions during baseline and followed by vehicle or RGFP966 injections (n=23). Error bars indicate the standard error of the mean. The main effect of group was not reliable and did not interact with lever or time block.

Figure 3.. Effects of post-session RGFP966 on extinction and reinstatement.

(A) Average active and inactive lever presses during the first two extinction sessions (shown in 15-min time blocks). Two groups received a 30-min session duration in Extinction Session 1 followed by either injection of RGFP966 (n=7) or Vehicle (n=8). A third group received a 2-hr extinction session followed by Vehicle (n=8). All groups received a 2-hr extinction session the next day (Ext 2). Extinction across 2-hr sessions are shown for (B) Sessions 1–12 and (C) Sessions 13–23, which occurred between reinstatement sessions. (D) Responding during the first 12 extinction. (C) Responding during each extinction session prior to reinstatement and during reinstatement testing in a novel context (CTX), with the cue previously associated with cocaine (CUE), and following a priming injection of cocaine (COC). Error bars indicate the standard error of the mean (±SEM). * p<0.05 (see text for statistical details).